RT Journal Article SR Electronic T1 Polyglutamine Disease Toxicity Is Regulated by Nemo-like Kinase in Spinocerebellar Ataxia Type 1 JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP 9328 OP 9336 DO 10.1523/JNEUROSCI.3465-12.2013 VO 33 IS 22 A1 Hyoungseok Ju A1 Hiroshi Kokubu A1 Tiffany W. Todd A1 Juliette J. Kahle A1 Soeun Kim A1 Ronald Richman A1 Karthik Chirala A1 Harry T. Orr A1 Huda Y. Zoghbi A1 Janghoo Lim YR 2013 UL http://www.jneurosci.org/content/33/22/9328.abstract AB Polyglutamine diseases are dominantly inherited neurodegenerative diseases caused by an expansion of a CAG trinucleotide repeat encoding a glutamine tract in the respective disease-causing proteins. Extensive studies have been performed to unravel disease pathogenesis and to develop therapeutics. Here, we report on several lines of evidence demonstrating that Nemo-like kinase (NLK) is a key molecule modulating disease toxicity in spinocerebellar ataxia type 1 (SCA1), a disease caused by a polyglutamine expansion in the protein ATAXIN1 (ATXN1). Specifically, we show that NLK, a serine/threonine kinase that interacts with ATXN1, modulates disease phenotypes of polyglutamine-expanded ATXN1 in a Drosophila model of SCA1. Importantly, the effect of NLK on SCA1 pathology is dependent upon NLK's enzymatic activity. Consistent with this, reduced Nlk expression suppresses the behavioral and neuropathological phenotypes in SCA1 knock-in mice. These data clearly indicate that either reducing NLK enzymatic activity or decreasing NLK expression levels can have beneficial effects against the toxicity induced by polyglutamine-expanded ATXN1.